Note: Descriptions are shown in the official language in which they were submitted.
2~
The invention relates to derivatives of 9-fluoropre-
nisolone, a process for their production and pharmaceutical
preparations containing these active substances.
9-Fluoroprednisolone (9~-fluoro-11~,17~,21-trihydroxy-
1,4-pregnadiene-3,2-dione) has been known for a long time. (See,
for example, J. Amer. Chem. 50c., 77, 1955, 4181). This corti-
coid is not a suitable active substance for pharmaceutical
preparations which are used Eor the topical treatment of
~ inflammatory diseases since it has very strong systemic effects.
The present invention is based on the observation tha-t
hitherto known derivatives of 9-fluoroprednisolone have only
weak systemic action but, when administered ~opically, they have,
surprisingly, a strong anti-inflammatory action that generally
exceeds that of the most effective commercial corticoids.
The present invention provides a derivative of 9-
fluoroprednisolone of the general formula (I)
H2X
C=O
H0 ~` \ ~ ~ ; ~ ORl (I)
oJ\~ '
wherein Rl represents a group of the general formula RC0- in
which R represents a hydrogen atom or an alkyl group or a cyclo-
alkyl or cycloalkylalkyl group or an alkyl-substituted cycloalkyl
or cycloalkylalkyl group, and Rl has~from 1 to 8 carbon atoms,
or in which R represents an aryl or aralkyl group or an alkyl
substituted aryl or aralkyl group, and Rl has up to 9 carbon atoms
and X represents a fluorine or chlorine atom or a group or the
general formula R'C00- which has from 3 to B carbon atoms and in
- 1 - ~ ,
~ A~ ~
which R' represents an alkyl group or a cycloalkyl or cycloalkyl-
alkyl group or an alkyl-substituted cycloalkyl or cycloalkyl-
alkyl group.
. Thus, for example, Rl may represent a formyl group or
an alkanoyl or cycloal~anoyl group having up to 8 carbon atoms
or a benzoyl group or a phenylalkanoyl group having up to 9 carbon
atoms, and X represent a fluorine or chlorine a~om or an alkanoyl
or cycloalkanoyl group having from 3 to 8 carbon atoms.
An acyl group represented by Rl and an acyloxy group
represented by X may be derived from a cyclic carboxylic acid or
from an open-chained tstraight-chained or branched-chained)
carboxylic acid, such as, for example, butyric acid, isobutyric
acid, valeric acid, isovaleric acid, trimethylacetic acid,
caproic acid, t-butylacetic acid, cyclopentanecarboxylic acid,
cyclohexanecarboxylic acid or caprylic acid or, in the case of
Rl, from formic acid, acetic or propionic acid.
Particularly preferred alkanoyl groups Rl and alkanoy-
loxy groups X are those that are derived from an alkanecarboxylic
acid containing up to 6 carbon atoms.
9-Fluoroprednisolone derivatives of the general formula
~I) where X represents a chlorine atom, are for example:
17a-acetoxy-21-chloro-9a-fluoro-11~-hydroxy-1,4-pregnadiene
3,20-dione,
21~chloro-9a-fluoro-11~-hydroxy-17a-propionyloxy-1,4-pregnadiene-
3,20-dione,
17a-butyryloxy-21-chloro-9a fluoro-11~-hydroxy-1,4-pregnadiene-
3,20-dione,
21-chloro-9a-fluoro-11~-hydroxy-17a-isobutyryloxy-1,4-pregnadiene-
3,20-dione,
21-chloro-9a-fluoro-11~-hydroxy-17a-valeryloxy-1,4-pregnadiene-
3,20-dione and
17a-benzoyloxy-21-chloro-9~-fluoro-11~-1,4-pregnadiene-3,20-
dione.
_ ~ _
9,21-Difluoroprednisolone derlvatives of the general formula
(I) are, for example,
17~-acetoxy-9~,21-difluoro~ hydroxy-1,4-pregnadiene-3,20-
dione,
9~,21-difluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-
3,20-dione,
17a-butyryloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3-20-
dione and
9~,21-difluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-
3,20-dione.
9-Fluoroprednisolone derivatives of the general formula (I) with
X representing a group of the formula R'COO- are preferably those
in which the radicals Rl and X together have 5 to 14 carbon
atoms. Such fluoroprednisolone derivatives are, for example:
17~-acetoxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-pregnadiene-
3,20-dione,
17~-acetoxy-21-butyryloxy-9~-fluoro-11~-1,4-pregnadiene-3,20-
dione,
17~,-acetoxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregna~
diene-3,20-dione,
17~-acetoxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-
3,20-dione,
21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-1,~-pregnadiene-
3,20-dione,
17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregna-
diene-3,20-dione,
9~-fluoro-11~-hydroxy-17~,21-diisobutyryloxy-1,4-pregnadiene-
3,20-dione and
9~-fluoro-11~-hydroxy-17~,21-divaleryloxy-1,4-pregnadiene~3,20-
dione.
The present .invention also provides a process for the
manufacture of the 9-fluoroprednisolone derivatives of the
ene-al formula (I~ wherein
a) the epoxide ring of a compound of the general
formula (II)
CH2X
I
~ ~ (II),
l J
~```~/ ' .
o \~
in which Rl and X have the meanings given above is opened with
hydrogen fluoride, or
b) a 9-fluoro derivative of the general formula (III)
C-O
HO ~ ~, ~ 1 (III)
~ ~
od~
in which Rl has the meaning given above, i5 halogenated or
esterified in the 21-position, or
c) for the production of a 9-fluoroprednisolone
derivative of the general formula (I) wherein
X represents a fluorine or chlorine atom, an
ortho ester of the general formula (IV)
CH2 R2
`\, /
co c
/ \
. ~ _O R3 (IV),
~ . /~
wherein R3 represents a hydrogen atom, an alkyl group or a
cycloalkyl group having up to 7 carbon atoms or a phenyl group
and R2 represents an alkyl group having 1 to 4 carbon atoms, is
cleaved with a trimethylsilyl halide or a triphenylmethyl halide.
The process of the invention according to process
variants (a) and ~b) may be carried out in a manner known per se
under the conditions described in U.S. Specifications Nos.
3,678,034, 3,718,671 and 3,828,083. The starting compounds for
these processes may be produced under the conditions described
in U.S. Specification No. 3,152,154 and in German Offenlegung-
sschriften Nos. 23,40,591 and 20,55,221.
The process of the invention according to process
variant (a) may likewise be carried out under conditions known
per se preferably by reacting a compound of general formula (II)
with hydrogen fluoride contained in an inert solvent. Suitable
inert solvents are, for example, ethers (e.g. diethyl ether,
diisopropyl ether~ tetrahydrofuran or pyridine) and chlorinated
hydrocarbons (e.g. methylene chloride, chloroform, carbon tetra-
chloride or tetrachloroethane).
The process of the invention according to process
variant (b) may likewise be carried out under conditions known
p se.
lZ4
~ h~s, for example, a ~ydroxy steriod of the genera~
formula (III) may be esterified with an acyl chloride or acid
anhydride in the presence of an acid, such as, for example,
hydrogen chloride, ~-toluenesulphonic acid or trifluoroacetic
acid, or in the presence of a base such, for example, as
potassium carbonate, pyridine, collidine or _-dimethylamino-
pyridine.
A preferred method of chlorinating a compound of the
general formula (III) comprises esterifying the 21-hydroxy group
with a sulphonic acid, preferably with methanesulphonic acid or
p~toluenesulphonic, and then exchanging the sulphonic acid group
or chlorine. The 21-hydroxy group is esterified, for example,
by causing a sulphonic acid chloride to act on tlle compound of
formula ~III) in the presence of an organic base, such, for
example, as pyridine, or in the presence of an aqueous alkali,
The sulphonic acid group is exchanged for a chlorine atom pre-
ferably by reacting the 21-sulphonic acid ester with an alkali
metal chloride such as, for example, lithium chloride, in the
presence of a polar solvent such, for example, as dimethylfor-
mamide.
The process of the invention according to processvariant (c) may likewise be carried out under conditions known
per se.
~=.~ = = _
The cleavage of an ortho ester of the general formula
(IV) is preferably effected with trimethylsilyl fluoride, tri-
¦ methylsilyl chloride or triphenylmethyl chloride, advantageously
in an inert solvent such, for example, as a dipolar aprotic
solvent (e.g. dimethylformamide, N-methylpyrrolidone, dimethyl
sulphoxide or hexamethylphosphoric acid triamide), an ether
(e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxan
or glycol dimethyl ether), a chlorinated hydrocarbon (e.g.
methylene chloride, chloroEorm or tetrachloroethane), a hydro~
carbon (e.g. benzene, toluene or cyclohexane) or a mixture of any
two or more of these solvents.
The starting compound for the process according to the
invention can thus be produced in a simple manner and with hiqh
yields from prednisolone which can itself be synthesised relativ-
ely easily from diosgenin. The result o~ this is -that compounds
of the invention can be produced from diosgenin at relatively
low expenditure and with a total yield of approximately 15%~ In
contrast, the syntheses of the known highly effective corticoids
from diosgenin requlre considerably more expendi-ture and the total
yields obtained are significantly lower (approximately 0.5 to 5%).
In view of the growing difficulties in obtaining a sufficient
quantity of suitable starting materials for the corticoid
syntheses and with regard to the high cost of active substances,
which is the disadvantage of corticoid-containing medicament
specialities, this is not without significance.
As already mentioned, when the compounds oE the
invention are administered topically they have a very strong
anti-inflammatory activity but have only weak action when
administered systemically.
The anti-inflammatory activity was determined as
follows: A hyperaemia was produced on human skin in the following
manner.
Part of the S-tratum corneum on the backs of male and
female volunteers was stripped off by applying and tearing off
20 times from the same place a portion of "Tesa" (~egistered
Trade Mark) self-adhesive tape 2 cm wide and a pronounced hyper~
aemia was thus produced.
Approximately 50 mg of the ointment preparations were
applied to marked 4 cm2 zones inside the stripped area.
In order to obtain comparable starting values relative
numbers were used since the colour of the untreated skin, as also
the reddening of the hyperaemic area, differs from case to case.
The colour value of the untreated skin was se-t at 100
and that of the stripped skin at 0.
The skin colour value of the skin under vasoconstric-
tion (100) was determined on a relative scale.
Relatively slight, average and a high degree of vaso-
constriction was rated accordingly between 0 and 100.
The average values, which were derived from investi-
gations of the various test persons and from various regions of
the back, are given in the following Table A.
The system activity of the compounds was determined
using the adjuvant-oedema test as follows:
SPF rats weighing 130 to 150 g were injected in the
right hind leg with 0.1 ml of a 0.5~ Mycobacterium butyricum
suspension (obtainable from the American firm Difko) in order to
produce a focus of inflammation. The volume of the rats' legs
was measured before injection and again 24 hours after injection
to determine the extent of the oedema. Different quantities of
the test substance were then administered orally to the rats.
After a further 24 hours the volume of the legs was determined
once a~ain.
From the leg volumes obtained the quantity of test
substance necessary to achieve 50~ healing of the oedema in the
leg was determined in the normal manner.
The results obtained in the tests are given in the
following Table A:
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C C H H r O
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X ~ w ~ ~ w tD ~D ~ W ~ ~2 ~
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Similar results are obtained if the systemic activity
of the 9-fluoroprednisolone derivatives according to the invention
is determined using the known thymolysis test or the known sodium/
potassium retention test.
In combination with the carriers conventionally used in
galenical pharmacy compounds of the invention are suitable for
the local treatment of contact dermatitis, eczemas of the most
varied types, neurodermatoses, erythrodermia, burns, Pruritia
vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen
_
ruber planus et verrucosus and similar skin diseases.
~_ _ _
Accordingly, the present invention also provides a
pharmaceutieal preparation which comprises a compound of the
general formula (I), in admixture or conjunction with a pharma-
ceutically suitable carrier.
The pharmaceutical preparations may be produced in a
eonventional manner by converting the active substanees with
suitable additives into the desired form of administration, such
as, for example, solutions, lotions, ointments, creams or
plasters. In the preparations formulated in -this manner the con-
eentration o aetive substance depends on the form of administrat-
ion. An active substance concentration of 0.001 to 1~ is
preferably used in the case of lotions and ointments.
The present invention further provides a method of
treating an animal to relive inflammation, which comprises
applying a compound or preparation of the invention to the
affected area.
In addition, compounds of the invention, optionally in
combination with the conventional carriers and auxiliary agents,
are also very suitable for the production of inhalants which
can be used for the therapy of allergic diseases of the res-
piratory system, such as, for example, bronchial asthma or
rhinitis.
- 11 -
i
¦ A eompound or preparation of the present invention may
also be used to alleviate inflammation caused by a medicament
used for treating a non-inflammatory disease.
Aeeordingly, the present invention provides a pharma-
eeutieal composition which comprises a compound of the general
! formula (I) in admixture with a medicament for the treatment of
a non-inflammatory disease but which i5 liable to have an
inflammatory aetion, and a pharmaceutical preparation which
eomprises this eomposition in admixture or conjunetion with a
¦ 10 pharmaeeutieally suitable carrierO
¦ The present invention further provides a pack which
¦ eomprises a eompound of the general formula (I), or a pharma-
I eeutieal preparation containing this, and a medicament for the
¦ treatment of a non-inflammatory disease but which is liable to
¦ have an inflammatory action.
¦ The following Examples illustrate the invention:
I-5yntheses
Example 1
a) 5 g of 9~-fluoroprednisolone are added to 500 mg of
pyridine tosylate, twice concentrated to dryness ln vacuo with
benzene, in 500 ml of benzene and 40 ml of N,N-dimethylformamide.
At a bath temperature of 130C 50 ml of solvent are distilled
off and 6 ml of orthoacetic acid triethyl ester are added. The
remainder of the benzene is distilled off within 2.5 hours and
after the addition of 2.4 ml of pyridine the whole is concen-
trated in vacuo. 17~,21-~1-ethoxyethylidenedioxy)-9~fluoro-
ll~-hydroxy-1,4-pregnadiene-3,20-diane is isolated as a yellow
oily epimer mixture.
b) A solution of the oil thus obtained in 150 ml of
methanol is refluxed for 1 hour at 90C with a mixture of 54 ml
of 0.1 N acetic acid and 6 ml of 0.1 N aqueous sodium acetate
solution. The mixture is concentrated to dryness in vacuo, added
- 12 -
2~
to water and extracted with ethyl acetate. The organic extracts
are washed with water, dried and evaporated in vacuo. Yield:
9 g of 17~-acetoxy-9~-fluoro-11~-21-dihydroxy-1,4-pregnadiene-
3,20-dione as a foam.
c) 3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4
pregnadiene-3,20-dione are stirred in 17 ml of pyridine and 8 ml
of propionic anhydride for 1.5 hours at room temperature. After
precipitating with ice water filtration is effected, the residue
~ is taken up in methylene chloride and is evaporated after washing
and drying over sodium sulphate. 4.9 g are isolated which are
chromatographed on 450 g of silica gel with a methylene chloride/
acetone gradient (0-15~ acetone). Yield: 2.96 g of 17~x-acetoxy-
9~-fluoro-11~-hydroxy 21-propionyloxy-1,4-pregnadiene-3,20-dione.
Melting point 219C. [~]25 = +81 (pyridine). UV: ~239 =
(methanol).
Example 2
4.5 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4-
pregnadiene-3,20-dione are stirred overnight at room temperature
in 50 ml of pyridine and 25 ml of butyric anhydride. The
reaction product is precipitated with ice water, filtered off
and dissolved in methylene chloride. The solution is washed
with water, dried over sodium sulphate and concentrated in vacuo.
The residue is chromatographed on 700 g of silica gel with a
me~h."e~e
~1~ mc~y~chloride/acetone gradient (0-15% acetone). Yield: 3.6 g
of 17~-acetoxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-pregn-
adiene-3,20-dione. Melting point 218C.
Example 3
1.0 g of 17~-acetoxy 9~-fluoro~ -21-dihydroxy-1,4-
pregnadiene-3,20-dione is reacted as in Example 2 ~n 10 ml of
pyridine with 6 ml of valeric anhydride instead of butyric
anhydride. Yield: 680 mg of 17~-acetoxy-9~-fluoro-11~-hydroxy-
21-valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 213C.
- 13 -
Example 4
3.0 g of 17~-acetoxy~9~-fluoro 11~,21-dihydroxy-1,4-
pregnadiene-3,20-dione in 30 ml of pyridine are stirred with 15
ml of caproic anhydride for 1.5 hours at room temperature. The
mixture is worked up as in Example 2. The crude product is
purified on 450 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). 2.36 g of 17~-ace-toxy-9~-
fluoro-21-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dioneO
Melting point 222C. [~]D = ~ (pyridine). UV: E239 - 15500
(methanol).
Example 5
.
3.0 g of 17~-acetoxy-9~-fluoro-11~,21-dihydroxy-1,4-
pregnadiene-3,20-dione are stirred with 15 ml of trimethylacetic
anhydride in 30 ml of pyridine for 48 hours at room temperature.
As described in Example 2 ! the crude product is isolated and
chromatographed on 700 g of silica gel with a methylene chloride/
acetone gradient (0-12~ acetone). Yield: 2.06 g of 17~-acetoxy-
9~-fluoro-11~-hydroxy-21-trimethylacekoxy-1,4-pregnadiene-3,20-
dione. Melting point 227C. 1~]D5 = +79 (pyridine). W: ~239 =
15500 (methanol).
E ample 6
5.0 g of 9~-fluoro-11~-21-dihydroxy-17~-propionyloxy-
1,4-pregnadiene-3,20-dione, produced as in Example la and lb from
9~-fluoroprednisolone using orthopropionic acid triethyl ester
instead of orthoacetic acid triethyl ester, are stirred in 50 ml
of pyridine with 25 ml of propionic anhydride for 2 hours at
room temperature. The mixture is worked up as described in
Example 2. 4.8 g of crude product are purified on 450 g of
silica gel with a methylene chloride/acetone gradient (0-15%).
Yield: 4.62 g of 9~~fluoro~ -hydroxy-17~,21-dipropionyloxy-
1,4-pregnadiene~3,20-dioneO Melting point 191C. [~]D ~ ~51
(chloroform). UV: ~239 = 15700 (methanol).
2~
Example 7
5.0 og 9(x-fluoro-11~,21-dihydroxy-17r~-propionyloxy-
1,4-pregnadiene~3,20-dione are reacted as in Example 2 with
butyric anhydride. The crude product is chromatographed on 450 g
of silica gel with a methylene chloride/acetone gradient (0-12
acetone). 4.93 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-
propionyloxy-1,4-pregnadiene-3,20 dione. Melting point 179C.
1~]D = +51 ~chloroform). W : ~239 = 15700 (methanol).
Example 8
_ .
5 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-
1,4-pregnadiene-3,20-dione are reacted as in Example 2 with valeric
anhydride ins-tead of butyric anhydride. The whole is likewise
worked up as described in Example 2. The crude produce is
purified on 750 g of silica gel with a methylene chloride/acetone
gradient (0-15% acetone). Yield: 5.03 g of 9(Y-fluoro-ll~-
hydroxy-17~-propionyloxy-21-valeryloxy-1,4-pregnadiene-3,20-
dione. Melting point 190C. [a]D = +54 ~chloroform).
W: ~239 = 15800 (methanol).
Example 9
5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-
1,4-pregnadiene-3,20-dione are reacted as in Example 2 with
caproic anhydride instead of butyric anhydride. The crude pro-
duct weighing 5.8 g is purified on 700 g of silica gel with a
methylene chloride/acetone gradient (0-12~ acetone). 4.32 g of
9~-fluoro-21-hexanoyloxy-11~-hydroxy-17~-propionyloxy-1~4-
pregnadiene-3,20-dione are isolated. Melting point 208C.
[~]D = +52 (chloroform). W : E239 - 15900 (methanol).
Example_10
5.0 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-
1,4-pregnadiene-3,20-dione are reacted and worked up as in Example
2 with trimethylacetic anhydride instead of butyric anhydride
5.9 g of crude product are chromatographed on 450 g of silica
~ 15 -
LZ~
gel with a methylene chloride/acetone gradient (0-12~ acetone).
Yield: 2.23 g of 9~-fluoro~ -hydroxy-17~-propionyloxy-21-
trimethylacetoxy-1,4-pregnadiene-3,20-dione. Meltin~ point
214C. [~]25 = +53o (chloroform). W : ~2~9 = 15700 (methanol).
Example 11
~___ _
a) 25 g of 9~ fluoroprednisolone are stirred overnight at
room temperature in 250 ml of pyridine and 125 ml of butyric
anhydride. After precipitating with ice water filtration is
' effected and the residue is dissolved in methylene chloride. The
solution is washed in water, dried over sodium sulphate and
concentrated ln vacuo. The residue is chromatographed on 2.5 kg
of silica gel with a methylene chloride/acetone yradient (0-15
acetone). Yield: 23.1 g of 21-butyryloxy-9~-fluoro~ ,17~-
dihydroxy-1,4-pregnadiene-3,20-dione~
b) 100 ml of a 5% solution of methyl lithium in ether are
added dropwise at 0C under argon to a suspension of 24 g of
copper tI) iodide in 480 ml of dry tetrahydrofuran. The yellow
mixture is cooled to -30C and a solution of 22.3 g of 21-
butyryloxy-9~-rluoro-11~,17~-dihydroxy-1,4-pregnadiene-3,20-dione
in 400 ml of dry tetrahydrofuran is added. The whole is stirred
for 3 - 4 hours at this temperature. The excess reagent i5
destroyed with an aqueous ammonium chloride solution. ~fter
extraction with methylene chloride the organic phase is washed,
dried over sodium sulphate and evaporated in vacuo. Yield. 20.3
g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-1,4-pregnadiene-
3,20-dione.
c) 2.0 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted, worked up and purified as
in Example lc with propionic anhydride. 1.4 g of 17~-butyryloxy-
9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preynadiene-3,20-dione
are isolated. Melting point 146~C.
- 16 -
Example 12
1.5 g o~ 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene 3,20-dione are reacted as in Example 2 with
valeric anhydride instead of butyric anhydride to form 17~-
butyryloxy-9~-fluoro-11~-hydroxy-21-valeryloxy-1,4-pregnadiene-
3,20-dione. Melting point 220C.
Example 13
1.4 g of 17~-butyryloxy-9~-fluoro~ ,21-dihydroxy-
1,4-pregnadiene-3,20-dione are stirred overnight at room temper-
ature in 15 ml of pyridine and 10 ml of oenanthic anhydride.
The mixture is then stirred into ice water and extracted with
methylene chloride. The extract is washed ~Jith water, dried
over sodium sulphate and evaporated ln vacuo. The excess
oenanthic acid in the residue is removed by distillation with
steam. The crude product is chromatographed on 250 g of silica
gel with a methylene chloride/acetone gradient (0-12% acetone).
790 mg of 17~-butyryloxy-9~-~luoro-21-heptanoyloxy-11~-hydroxy-
1,4-pregnadiene-3,20-dione are isolated.
Example 14
4.5 g of 17~-butyryloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted as Example 2 except that
isobutyric anhydride is used instead of butyric anhydride. The
crude product is purified on 700 g of silica gel with a methylene
chloride/acetone gradient (0-12% acetone). Yield: 2.1 g of 17~-
butyryloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-pregnadiene-
3,20~dione.
Example 15
_
a) 3 g of 9~-fluoroprednisolone are stirred overnight at
room temperature in 30 ml of pyridine and 15 ml of valeric
anhydride. The mixture is then stirred into ice water and
extracted with methylene chloride. The extract is washed with
water, dried over sodium sulphate and evapora-ted 1n vacuo. The
excess valeric acid is removed from the residue by distillation
with steam. The crude product is chromatographed on 300 g of
silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.87 g of 9~-fluoro-11~,17~-dihydroxy-21-
valeryloxy-1,4-pregnadiene-3,20-dione.
b) 2 g of 9~-fluoro-11~,17~-dihydroxy-21-valeryloxy-1,4-
pregnadiene-3,20-dione are converted as in Example llb with
lithium dimethyl cupràte to form 1.86 g of 9~-fluoro-11~,21-
' dihydroxy-17~-valeryloxy-1,4-pregnadiene-3,20-dione.
c) 1.8 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-
1,~-pregnadiene-3,20-dione are reacted as in Example 2, except
that propionic anhydride is used instead of butyric anhydride,
to form 920 mg of 9~-fluoro-11~-hydroxy-21-propionyloxy-17(x-
valeryloxy-1,4-pregnadiene-3,20-dione. Melting point 206C.
E ample 16
3.4 g of 9~-fluoro-11~,21-dihydroxy-17~-valeryloxy-
1,4-pregnadiene-3,20-dione are treated as in Example 2 with
butyric anhydride and is worked up in an appropriate manner.
1.96 g of 21-butyryloxy-9~-fluoro-11~-hydroxy-17~-valeryloxy-
1,4-pregnadiene-3,20-dione are isolated. Melting point 234C.
Example 17
A solution of 2.0 g of 9~-fluoro-11~,21-dihydroxy-17~-
valeryloxy-1,4-pregnadiene-3,20-dione in 20 ml of pyridine is
stirred with 10 ml of caproic anhydride for 1.5 hours at room
temperature. The reaction product is precipitated with ice water,
filtered off and dissolved in methylene chloride. The solution
is washed with water, dried and evaporated ln vacuo. The residue
1.96 g of crude product, is chromatographed on 200 g of silica
gel with a methylene chloride/acetone gradient (0-12% acetone~.
Yield: 1.58 g of 9~fluoro-21-hexanoyloxy-11~-hydroxy-17~-
valeryloxy-1,4-pregnadiene-3/20-dione.
- - 18 -
2~
E ample 18
a) 12 g of 9~-fluoroprednisolone are reacted as in
Example lla, except that isobutyric anhydride is used instead of
butyric anhydride, to form 10.4 g of 9~-fluoro~ ,17~-dihydroxy-
21-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 10 g of 9~-fluoro~ ,17~-dihydroxy-21-isobutyryloxy-
1,4-pregnadiene-3,20-dione are converted as in Example llb with
lithium dimethyl cuprate to form 6.9 g of 9~-fluoro-11~,21-
~ dihydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
c) 2.1 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryloxy-
1,4-pregnadiene-3,20-dione are reacted as in Example lc with
propionic anhydride to form 1.3 g of 9~-fluoro-11~-hydroxy-17~-
iso~utyryloxy-21-propionyloxy-1,4-pregnadiene-3,20-dione.
Example 19
_ _
1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-isobutyryIoxy-
1,4-pregnadiene-3,20-dione are reacted with butyric anhydride,
worked up and chromatographed as in Example 2. 670 mg of 21-
butyryloxy-9~-fluoro-11~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-
3,20-dione are isolated.
Example 20
a) 5.0 g of 9~-fluoro-11~,17~-dihydroxy-21--trimethyl-
acetoxy-1,4-pregnadiene-3,20-dione are converted as in Example
llb with lithium dimethyl cuprate to form 3.4 g of 9~-fluoro-
11~,21-dihydroxy-17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione~
b) 2.4 g of 9~-fluoro-11~,21-dihydroxy-17~-trimethyl-
acetoxy-1,4-pregnadiene-3,20-dione are reacted as in Example lc
with propionic anhydride to form 1.2 g of 9~-fluoro-11~-
hydroxy-21-propionyloxy-17~-trimethylacetoxy~1,4-pregnadiene-
3,20-dione.
Example 21
3.1 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione produced from 9~-fluoroprednisolone
-- 19 --
29~
as in Example la and lb using orthobenzoic acid triethyl ester
instead o~ orthoacetic acid triethyl ester are stirred in 30 ml
of pyridine and 15 ml of propionic anhydride for 1 hour at room
temperature. The whole is worked up as in Example lc. The
crude product is purified on 450 g of silica gel with a methylene
chloride/acetone gradient (0-12% acetone). Yield: 1.34 g of
17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-propionyloxy-1,4-preg-
nadiene-3,20-dione. Melting point 235C (decomposition).
~ [~]25 = +22 (pyridine). UV: ~234 = 28800 (methanol).
Example 22
3.0 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted and worked up as in
Example 2 in 30 ml of pyridine and 15 ml of butyric anhydride.
After purifying the crude product on 450 g of silica gel with a
methylene chloride/acetone gradient (0-12~ acetone). 1.9 g of
17~-benzoyloxy-21-butyryloxy-9~-fluoro-11~-hydroxy-1,4-preg-
nadiene-3,20-dione are isolated. Melting point 218C (decompos-
ition). [~]D5 = +21 (pyridine). UV: ~234 = 28900 (methanol).
Example 23
2.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted and worked up as in
Example 2 except that valeric anhydride is used instead of
butyric anhydride. The crude product is purified on 450 g of
e f ~J~ e
silica gel with a meth,~ chloride/acetone gradient (0-12% acetone).
1.81 g of 17~-benzoyloxy-9~~fluoro-11~-hydroxy-21-valeryloxy
1,4-pregnadiene-3,20-dione are obtained. Mel-ting point 208~C.
I~]25 = +22 (pyridine). UV: ~234 = 29000 (methanol).
Example 24
2.1 g of 17~~benzoyloxy-9~-fluoro~ ,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted and worked up as in Example
2 with isobutyric anhydride instead of butyric anhydride. The
crude product is chromatographed on 200 g of silica gel with a
-- ~0 --
methylene chloride/acetone gradient (0 12% acetone3. 1.09 y of
17~~~enzoyloxy-9~-fluoro-11~-hydroxy-21-isobutyryloxy-1,4-
pregnadiene-3,20-dione are obtained.
Example 25
1.8 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are reacted as in Example 2 with
trimethylacetic anhydride instead of butyric anhydride, worked
up in an appropriate manner and chromatographed as described in
Example 2. 720 mg of 17~-benzoyloxy-9~-fluoro-11~-hydroxy-21-
trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
Example 26
10 ml of hexamethylphosphoric acid triamide are
stirred with 1.3 ml of thionyl chloride for 30 minutes at 0C.
800 mg of 17~-acetoxy-9u-fluoro-11~,21-dihydroxy-1,4-pregnadiene-
3,20-dione are then added and stirring is continued for 5.5
hours at 0C. The mixture is added to ice water, extracted with
ethyl acetate and the extracts are washed neutral with sodium
hydrogen carbonate and water. The whole is dried over sodium
sulphate and after concentration in vacuo 1 g of crude product
is isolated which is purified on 65 g of silica gel with a
methylene chloride/acetone gradient ~0-15~ acetone). Yield:
535 mg of 17~-acetoxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-
pregnadiene-3,20-dione. Melting point 265C tdecomposition).
[~]25 = +101 ~pyridine). UV: ~239 = 15800 (methanol)~
Example _
1.2 g of 9~-fluoro-11~,21-dihydroxy-17~-propionyloxy-
1,4-pregnadiene-3,20-dione are reacted with thionyl chloride in
hexamethylphosphoric acid triamide as in Example 26. The crude
product is chromatographed on 150 g of silica gel with a methyl-
ene chloride/acetone gradient (0-15~ acetone). Yield: 860 mg of
21-chloro-9~ fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-
3,20-dione. Melting point 229C (decomposition). [~]D ~ +98
~4~
(pyridine). W: ~239 = 15900 (methanol).
Example 28
___
950 mg of 9~-fluoro-11~,21-dihydroxy-17(~-isobutyryloxy-
1,4-pregnadiene-3,20-dione are treated as in ~xample 26 with
thionyl chloride in hexamethylphosphoric acid triamide. The
crude product is purified on 120 g of silica gel with a methylene
chloride/acetone gradient (0-15~ acetone). Yield: 520 mg of
21-chloro-9~-fluoro~ -hydroxy-17~-isobutyryloxy-1,4-pregnadiene-
3,20-dione. Melting point 216~C.
Example 29
2.5 g of 17~-benzoyloxy-9~-fluoro-11~,21-dihydroxy-
1,4-pregnadiene-3,20-dione are are reacted as in Example 26 and
the crude product is purified on 250 g of silica yel with a
methylene chloride/acetone gradient (0-12% acetone). Yield:
1.1 g of 17~-benzoyloxy-21-chloro-9~-fluoro-11~-hydroxy-1,4-
pregnadiene-3,20-dione. ~elting point 256~C (decomposition).
[~]D5 ~ ~15 (pyridine). UV: E234 = 28600 tme-thanol).
Example 30
a) A suspension of 8.7 g of 21-fluoro-17~-hydroxy-1,4,9
(11)-pregnatriene-3,20-dione in 100 ml of diethylene glycol
dimethyl ether is stirred with 12 g of N,N-dimethylaminopyridine
and 8.8 ml of acetanhydride for 6.5 hours at 80~C. The reaction
mixture is diluted with methylene chloride and washed with 2 N
hydrochloric acid. After distillation with steam extraction is
effected with methylene chloride drying is effected over sodium
sulphate and afker evapora-tion 7.9 g of 17u-acetoxy-21-fluoro-
1,4,9(11)-pregnatriene-3,20-dione are iso]ated.
b) 7.6 of 17~-acetoxy-21-fluoro-1,4,9(11)-pregnatriene-
3,20-dione are dissolved in 7h ml of dioxan and 7.2 g of N~
bromo-succinimide are added. After the dropwise addition of 38
ml of 10% aqueous perchloric acid stirring is continued for 30
minutes at room temperature and the reaction solution i5 added
- 22 -
to a solution of 3.5 g of sodium hydrogen sulphite in 350 ml of
water. The precipitate ls sucked off and 10 g of 17~1-acetoxy-
9~-bromo-21-fluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione are
obtained after drying.
c) 10 g of ~he above crude product are refluxed for 2
hours at 110C in 600 ml of ethanol with 14.0 g of potassium
acetate. The reaction solution is concentra-ted ln vacuo and is
added to ice water. The precipitate is filtered off and the
' crude product is purified on 700 g of silica gel with a methylene
chloride/acetone gradient (0-6% acetone). Yield: 3.4 g of 17~-
acetoxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
d) 31 ml of a 70% (~IF) /pyridine solutioIl are cooled to
-60C and a solution of 3 g of 17~-acetoxy-9,11~-epoxy-21-fluoro~
1,4~pregnadiene-3,20-dione in 3 rnl of pyridine is added~ The
reaction solution is stirr~d for 10 hours at -5C and then
stored for 3 days in a refrigerator. The whole is added to
ammoniacal ice water and the precipitate is filtered off. The
crude product is purified on 350 g of silica gel with a methylene
chloride/acetone gradient (0-15% acetone). Yield: 2.15 y of
17~-acetoxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-
dione. Melting point 276C (decomposition) [~]D = +16
(chloroform). W: ~239 = 15800 (methanol).
Example 31
a) 5 g of 21-fluoro-17~-propionyloxy-1,4,9(11)-pregnatriene-
3,20-dione are produced as in Example 30a from 7~9 g of 21-fluoro-
17a-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and propionic
anhydride and these 5 g are reacted with N-bromo-succinimide
under the conditions described in Example 30b. Yield: 8.5 g of
9~-bromo-21-fluoro-11~-hydroxy-17~-propionyloxy-1,4-pregnadiene-
3,20-dione.
b) 8.5 g of the above crude product are reacted with
potassium acetate under the conditions described in Example 30c.
- 23 -
The crude product is purified on 700 g of silica gel with a
methylene chloride/acetone gradient (0-6% acetone). Yield: 5.3
g of 9,ll~~epoxy-21~fluoro-17~-propionyloxy-1,4-preynadiene-
3~20-dione.
c) 5.0 g of 9,1]~-epoxy-21-fluoro--17~-propionyloxy-1,4-
pregnadiene-3,20-dione are treated as in r~xample 30d with 70~
(HF)n/pyridine solution. The reac-tion product is purified on
700 g of silica gel with a methylene chloride/acetone gradient
(0-15% acetone). Yield: 3.98 g of 9~,21-difluoro-11~-hydroxy-
17~-propionyloxy-1,4-pregnadiene-3,20-dione. Melting point
21~C. [~]25 = +15 (chloroform). UV: ~:239 = 15800 (methanol).
Example 32
a) 20.0 g of 17~-butyryloxy-21-fluoro-1,4,9(11)-pregna-
triene-3,20 dione, produced as in Example 30a from 21-fluoro-
17~-hydroxy-1,4,9~11)-pregnatriene-3,20-dione and butyric
anhydride, are treated with N-bromosuccinimide as in Example 30b.
Yield: 24.9 g of 9~-butyryloxy-21-fluoro-11~-hydroxy-1,4-
pregnadiene-3,20-dione.
b) The above crude product is treated with potassium
2Q acetate under the conditions described in Example 3c. 16.1 g of
17~-butyryloxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione
are isolated.
c) 15.1 g of 17~-butyryloxy-9,llR-epoxy-21-fluoro-1,4-
pregnadiene-3,20-dione are treated as in Example 30d with 70%
(HF)n/pyridine solution. The crude product is purified on 1.5
kg of silica gel with a methylene chloride/acetone gradient
(0-15% acetone). 13.4 g of 17~-bu~yryloxy-9~,21--difluoro~
hydroxy-1,4-pregnadiene-3,20-dione are obtained. Melting point
126C. 1~]25 = -~11 (chloroform). UV: ~239 = 15300 (methanol).
Example 33
a) 7.1 g of 21-fluoro-17~-valeryloxy-1,4,9(11)-pregnatriene-
3,20-dione are produced as in Example 30a from 9.0 g of 21-
- 2~ -
fluoro-17~-hydroxy-1,4,9(~ pregnatriene-3,20-dione and valeric
~ ob
anhydride and these 7.1 g are treated as in ~xample ffl with
N-bromosuccinimide. Yield: 8.7 g 9~-bromo-21-fluoro~ 3-
hydroxy-17~-valeryloxy-1,4-pregnadiene-3t20-dione.
b) 6.0 g of the above crude product are reacted as in
Example 30c with potassium acetate. After purifying the reaction
product on 700 g of silica yel with a methylene chloride/ace-tone
gradient (0-5~ acetone) 4.2 c~ of 9,llr~-epoxy-21-fluoro-17~-
~ valeryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.1 g of 9~,21-difluoro-11~-hydroxy-17~-valeryloxy-
1,4-pregnadiene-3,20~dione are produced as in Example 30d by
the reaction of 3.8 g of 9,11~-epoxy-21-fluoro-17~-valeryloxy-
1,4-pregnadiene-3,20-dione with a 70% (~IF) /pyridine solution,
which 3.1 g are obtained after purification on 450 g of silica
gel with a methylene chloride/acetone gradient (0-15% acetone).
Melting point 139C. [~]D5 = +10 (chloroform). W: ~239 =
15800 (methanol).
Exam~le 34
a) Under the conditions described in Example 30a 7.3 y of
21-fluoro-17a-hexanoyloxy-1,4,9(11)-pregnatriene-3,20-dione are
produced from 8.9 g of 21-fluoro-17~-hydroxy-1,4,9(11)-preg-
natriene-3,20-dione and caproic anhydride which 7.3 g are reacted
as in Example 30b with N-bromosuccinimide~ Yield: 8.2 g of 9~-
bromo-21-fluoro-17~-hexanoyloxy~ -hydroxy-1,4-preynadiene-
3,20-dione.
b) 8.0 g of the above crude product are treated as in
Example 30c wi-th potassium acetate and the crude product is
purified with a methylene chloride/acetone yradient (0-5~ acetone).
5.8 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-pregnadiene-
3,20-dione are isolated.
c) 3.2 g of 9,11~-epoxy-21-fluoro-17~-hexanoyloxy-1,4-
pregnadiene-3,20-dione are treated, as described in Example 30d,
- 25 -
with a 70% ~HF) /pyridine solution. The reaction product is
purified on 350 g of silica gel wlth a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.6 g of 9~,21-difluoro-
17~-hexanoyloxy-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 35
.
a) 6.2 g of 21-fluoro-17(x-isobutyryloxy-1,4,9~ preg-
natriene-3,20-dione are produced as in Example 30a from 8.1 g of
21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione and
isobutyric anhydride, which 6.2 g are reacted as in Example 30b
with N-bromosuccinimide. Yield: 6.9 g of 9~-bromo-21-fluoro-
ll~-hydroxy-17~-isobutyryloxy-1,4-pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in
Example 30c with potassium acetate and the reaction product is
purified on 600 g of silica gel with a methylene chloride/acetone
gradient (0-5% acetone). 4.1 g of 9,11~-epoxy-21-fluoro-17~-
isobutyryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-isobutyryloxy-1,4-
pregnadiene-3,20-dione are reacted as in Example 30d with a 70%
(HF)n/pyridine solution. The crude product is purified on 400 g
of silica gel with a methylene chloride/acetone gradient (0-15%
acetone). Yield: 2.9 g of 9~,21-difluoro-11~-hydroxy-17(~-
isobutyryloxy-1,4-pregnadiene-3,20-dione.
Example 36
. _
a) 8.0 g of 21-fluoro-17(1-hydroxy-1,4,9(11)-pregnatriene-
3,20-dione are added to a mixture of 80 ml of isovaleric acid
and 32 ml of tri~luoroacetic anhydride and then stirred for 2.5
hours at 80C. The whole is then added to hot water in order to
destroy the excess anhydride and is aEterwards extracted with
methylene chloride. After neutralising with 1~ pyridine/water
and drying over sodium sulphate the whole is evaporated in vacuo.
The substance is dissolved in small quantity of pyridine, added
to ice water and the pyridine is neutralised with dilute hydro-
- 26 -
chloric acid. After working up in the usual manner 5.8 g of
21-fluoro-17~-isovaleryloxy-1,4,9(11)-preynatriene-3,20-dione
are isolated.
b) 5.3 g of 21-fluoro-17(1-isovaleryloxy-1,4,9(11)-
pregnatriene ~20-dione are treated as in Example 30b with N-
bromosuccinimide. 6.2 g of 9~-bromo-21-fluoro-11~-hydroxy-17~-
isovaleryloxy-1,4-pregnadiene-3,20-dione are obtained.
c) 6.0 g of the above crude product are reacted as in
' Example 30c with potasslum acetate. The reaction product is
purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5% acetone). Yield: 3.7 g of 9,11~-epoxy-
21-fluoro~17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
d) Under the conditions in Example 30d 3 g of 9~
epoxy-21-fluoro-17~-i`sovaleryloxy-1,4-pregnadiene-3,20-dione are
reacted with a 70~ (IIF) /pyridine solution. The crude product
is purified on 300 g of silica gel with a methylene chloride/
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21~difluoro-
ll~-hydroxy-17~-isovaleryloxy-1,4-pregnadiene-3,20-dione.
Example 37
.
a) As described in Example 30a 8.7 g of 21-fluoro-17~-
hydroxy-1,4,9tll)-pregnatriene-3,20-dione and trimethyl acetan-
hydride are reacted to form 6.3 g of 21-fluoro-17~-trimeth~l-
acetoxy-1,4,9~11)-pregnatriene-3,20-dione, which 6.3 9 are
treated as in Example 30b with N-bromosuccinimide. After working
up in the usual manner 6.5 g of 9~~bromo-21-fluoro-11~-hydroxy-
17~-trimethylacetoxy-1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in
Example 30c with potassium acetate and the crude product is
purified on 600 g of silica gel with a methylene chloride/
acetone gradient (0-5~ acetone). Yield: 3.1 g of 9,11~-epoxy-
21-fluoro-17~-trinlRthylacetoxy-1,4-pregnadiene-3,20-dione.
c) 1.9 g of 9~,21-difluoro-11~-hydroxy-17~-trimethyl-
- 27 -
acetoxy-1,4-pregnadiene-3,20-dione are produced as in Example
30d from 3.0 g of 9,11~-epoxy-21-fluoro-17~-trimethylacetoxy-
1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/pyridine
solution, which 1.9 g are obtained after purification on 300 g
of silica gel with a methylene chloride/ace-tone gradient
(0-15% acetone).
Example 38
.
a) 7 0 g of 21-fluoro-17~-~3~phenylpropiony]oxy)-1,4,9
(ll)-pregnatriene-3,20-dione are produced as in Example 30a from
15.4 g of 21-fluoro-17~-hydroxy-1,~,9(11)-pregnatriene-3,20-
dione and 3-phenylpropionic acid chloride, which 7.0 g are
reacted as in Example 30b with N-bromosuccinimide. Yield: 6~9 g
of 9~-bromo-21-fluoro-11~-hydroxy-17~-(3-phenyl-propionyloxy)-
1,4-pregnadiene-3,20-dione.
b) 6.5 g of the above crude product are reacted with
potassium acetate under the conditions of Example 30c. The crude
product is purified on 650 g of silica gel with a methylene
chloride/acetone gradient (0-5~ acetone). Yield: 3.8 g of 9,
ll~-epoxy-21-fluoro-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-
3,20-dione.
c) 3.5 g of 9,11~-epoxy-21-fluoro-17~-(3-phenylpropiony-
loxy)-l,~-pregnadiene-3,20-dione are treated as in Example 30d
with a 70% (HF)n/pyridine solution and the crude product is
purified on 400 g of silica gel with a methylene chloride/ ~;
acetone gradient (0-15% acetone). Yield: 2.1 g of 9~,21-
difluoro-ll~-hydroxy-17~-(3-phenylpropionyloxy)-1,4-pregnadiene-
3,20-dione.
Example 39
...
a) 5.8 g of 17~-cyclopentanecarbonyloxy-21-fluoro-1,~,9 L.
(11)-pregnatriene-3,20-dione are produced as in Example 36 from
9.1 g of 21-fluoro-17~-hydroxy-1,4,9(11)-pregnatriene-3,20-dione,
91 ml of cyclopentanoic acid and 44 ml of trifluoroacetic
- 28 -
2~
; anhydride, which 5.8 g are treated as in Example 30b with
~ N-bromosuccinimide. After working up in the normal manner 5.1
j g of 9~-bromo-17~-cyclopentanecarbonyloxy-21-fluoro-11~-hydroxy-i 1,4-pregnadiene-3,20-dione are isolated.
b) 6.0 g of the above crude product are reacted as in
Example 30c with potassium ace~ate and the crude product is
purified on 600 g of silica gel with a methylene chloride/acetone
gradient (0-5% acetone). 4.5 g of 17~-cyclopentanecarbonyloxy-
9,11~-epoxy-21-fluoro-1,4~pregnadiene-3,20-dione are obtained.
c) 4.0 g of 17~-cyclopentanecarbonyloxy-9,11~-epoxy-21-
fluoro-1,4-pregnadiene-3,20-dione are reacted as in Example 30d
with a 70% (IIF) /pyridine solution. The crude product is
purified on 400 g of silica gel with a methylene chloride/acetone
gradient (0-15~ acetone). Yield: 2.8 g of 17~-cyclopentane-
i carbonyloxy-9~,21-difluoro-11~-hydroxy-1,4-pregnadiene-3,20-dione.
Example 40
a) 5.8 g of 17~-cyclohexanecarbonyloxy-21-fluoro 1,4,9(11)-
pregnatriene-3,20-dione are produced under the conditions of
Example 36 from 9.2 g of 21-fluoro-17~-hydroxy-1,4,9(11)-
preqnatriene-3,20-dione, 92 ml of cyclohexanecarboxylic acid and
40 ml of trifluoroacetic anhydride, which 5.8 g are reacted as
¦ in Example 30b with N-bromosuccinimide. Yield. 6.1 g of 9~-
bromo-17~-cyclohexanecarbonyloxy-21-fluoro-11~-hydroxy 1,4-
pregnadiene-3,20-dione.
b) 6.0 g of the above crude product are reacted as in
¦ Example 30c with potassium acetate and the crude product is
! - purified on 600 g of silica gel with a methylene chloride/acetone
gradient (0-5% acetone). Yield: 3.4 g of 17~-cyclohexanecarbony-
loxy-9,11~-epoxy-21-fluoro-1,4-pregnadiene-3,20-dione.
c) 2.4 g o~ 17~-cyclohexanecarbonyloxy-9~,21-difluoro-
-hydroxy-1,4-pregnadiene-3,20-dione are produced as in Example
30d from 3.1 g of 17~-cyclohexanecarbonyloxy-9,11~-epoxy-21-
- 29 -
fluoro-1,4-pregnadiene-3,20-dione by reaction with a 70% (HF)n/
pyridine solution, which 2.4 g are obtained after purification
on 300 g of silica ~el with a methylene chloride/acetone
gradient (0-15% acetone).
Example 41
1 g of 17~,21-(1-ethoxybenzylidenedioxy)-9~ fluoro-
~ -hydroxy-1,4-pregnadiene-3,20-dione is stirred in 40 ml of
¦ dimethylformamide with 4 ml of trimethylsilyl fluoride for 2
¦ hours at room temperature. After precipitating with ice water
and working up in the usual manner the whole is evaporated ln
vacuo. The crude product is purified on 120 g of silica gel with
a methylene chloride/acetone gradient (0-10~ acetone). Yield:
240 mg of 17~-benzoyloxy-9~,21-difluoro-11~-hydroxy-1,4-
pregnadiene-3,20-dione.
II Pharmaceutical preparations
Example 42
3 Composition of an ointment
1 0.03~ of 9~-fluoro-11~-hydroxy-17~,21-dipropionyloxy-1,4-
pregnadiene-3,20-dione
` 20 2.50% Allercur hexachlorophenate, micronised, particle size
~ approximately 8 ~ (Allercur = Trade Mark for l-p-chlorobenzyl-
¦ 2-pyrrolidylmethylbenæimidazole)
6.00% Hostaphat ~W 340 (Trade Mark) (tert. ester of O-phosphoric
acid and wax alcohol tetra-glycol ether)
0.10% sorbic acid
j 10.00% neutral oil (Migloyol 812 (Trade Mark))
¦ 3.50~ stearyl alcohol
1.50% wool fat, anhydrous DAB 6
i 76.36% desalted water
Example 43
Production of an inhalant
1.000 g of micronised 9~-fluoro-11~-hydroxy-17~,21-
- 30 -
t
dipropionyl-oxy-1,4-pregnadiene-3,20-dione (average particle size
. smaller than 7 ~) and 39.00 g of ground lactose are mixed
à together. A dose of 20 mg of inhalant is used per inhalation.
~ .
1 10
!
,1
.
; 20
'
3 3o
- 31 -
